High intraepithelial expression of estrogen and progesterone receptors in the transformation zone of the uterine cervix

Abstract

OBJECTIVE: Because sex hormones may be involved in tumor initiation and progression, we analyzed the presence of hormone receptors in the transformation zone of the uterine cervix where the majority of human papillomavirus infections and associated (pre)neoplastic lesions develop. STUDY DESIGN: By using 23 total hysterectomy samples from young women who underwent surgery for noncervical benign uterine disease, we analyzed, by immunohistologic techniques, the in situ expression of estrogen (E 2 -R) and progesterone (P 4 -R) receptors in the transformation zone and ectocervix of the same women. RESULTS: The expression of estrogen receptors and progesterone receptors is significantly higher in the transformation zone compared with the ectocervix. Immunohistochemical localization indicated that hormone receptor-positive cells are mainly observed in (para)basal and intermediate cell layers in both the transformation zone and ectocervical epithelium. When transformation zone samples were segregated into epithelial tissues with a predominantly mature (7/23 samples) or immature (16/23 samples) squamous metaplasia, only biopsy specimens with immature squamous metaplasia showed a significantly higher density of hormone receptorpositive cells compared with ectocervical epithelium (P < .01). CONCLUSION: Our results suggest that the cervical transformation zone may be at increased risk of the development of cancer because of a high sensitivity to sex hormone regulation. Key words: Transformation zone, hormone receptor, uterine cervix, cancerA substantial majority of cancers and precursor lesions (squamous intraepithelial lesions; SILs) develop within a specific region of the cervix, the transformation zone (TZ), 1 where the glandular epithelium of the endocervix is transformed progressively into a squamous epithelium during a process called metaplasia, which can be considered as a stepwise progression of changes. In the first phase, endocervical "reserve" cells proliferate and stratify.2 After, these cells differentiate into squamous cells that initially have only a slightly increased amount of cytoplasm and which undermine the endocervical epithelium that is often seen as a residual layer on the surface (immature squamous metaplasia). Later, the cells may mature fully to squamous cells that are indistinguishable from the superficial cells of the ectocervix. 3The chronic infection of metaplastic keratinocytes of the TZ by oncogenic types of human papillomavirus (HPV) is associated with the induction of SIL, which may result in the development of cervical invasive cancer. 4 Despite the evidence that HPV is implicated strongly as the causative agent of cervical cancer, HPV infection alone is not sufficient for SIL development. In addition to immune, microbial, or chemical cofactors, 5-7 sex hormones may play a role in the development of SIL. Indeed, the variation of hormonal status that depends on age, pregnancy, or contraceptive use, has been shown to influence the development of cervical (pre)neoplastic lesions. [8][...

Variations of mitotic index in normal and dysplastic squamous epithelium of the uterine cervix as a function of endometrial maturation

“…[20][21][22] Nonetheless, it has long been recognized that cervical squamous epithelial cells contain sex-steroid receptors and hence, their proliferation and differentiation are influenced, to some extent, by the menstrual cycle and/ or sex-steroid hormonal levels. [20][21][22][23][24][25][26][27][28] Most studies have localized ERs and progesterone receptors (PRs), at minimum, to the basal and parabasal cell layers of the normal ectocervix. [20][21][22][23][24][25][26][27][28] Data on a possible correlation between the localization and the extent of ERs and the menstrual cycle phase are less homogeneous.…”

“…[20][21][22][23][24][25][26][27][28] Most studies have localized ERs and progesterone receptors (PRs), at minimum, to the basal and parabasal cell layers of the normal ectocervix. [20][21][22][23][24][25][26][27][28] Data on a possible correlation between the localization and the extent of ERs and the menstrual cycle phase are less homogeneous. Kanai et al 23 and Ciocca et al 22 both reported that the expression and localization of steroid hormone receptors did not vary significantly with the phase of the menstrual cycle.…”

Role of hormone cofactors in the human papillomavirus-induced carcinogenesis of the uterine cervix

“…Using K14-HPV16 transgenic mice in which the expression of HPV16 E6 and E7 oncogenes is driven by the keratin 14 promoter in the basal keratinocytes of the squamous epithelium, some investigators have shown that the TZ is five-fold more sensitive to the induction of squamous cell carcinogenesis by estrogen compared to other sites of the reproductive tract (Elson et al, 2000). We also found, by using immunohistological techniques and total hysterectomy samples from young women undergoing surgery for non-cervical benign uterine disease, that TZ biopsies with immature squamous metaplasia exhibit a significantly higher density of hormone receptor-positive cells compared to ectocervical epithelium, suggesting that the TZ may be at increased risk of developing (pre)neoplastic lesions because of a high sensitivity to sex hormone regulation (Remoue et al, 2003). Although endometrial expression of estrogen and progesterone receptors has been shown to vary during the menstrual cycle (Fujishita et al, 1997;Ravn et al, 1994), no significant difference was demonstrated in hormone receptor-positive cell density between the follicular and luteal phases in both TZ and ectocervical biopsies (Remoue et al, 2003).…”

“…We also found, by using immunohistological techniques and total hysterectomy samples from young women undergoing surgery for non-cervical benign uterine disease, that TZ biopsies with immature squamous metaplasia exhibit a significantly higher density of hormone receptor-positive cells compared to ectocervical epithelium, suggesting that the TZ may be at increased risk of developing (pre)neoplastic lesions because of a high sensitivity to sex hormone regulation (Remoue et al, 2003). Although endometrial expression of estrogen and progesterone receptors has been shown to vary during the menstrual cycle (Fujishita et al, 1997;Ravn et al, 1994), no significant difference was demonstrated in hormone receptor-positive cell density between the follicular and luteal phases in both TZ and ectocervical biopsies (Remoue et al, 2003). These data are in agreement with previous studies showing no significant variation, within the menstrual cycle, in hormone receptor concentrations in vaginal tissues (Schwartz, 2000) and in HPV-associated lesions (Monsonego et al, 1991), suggesting a lower sensitivity to menstrual cycle changes of genital squamous mucosa compared to glandular endometrial tissues.…”

The Normal Genital Tract of the Female California Sea Lion (Zalophus californianus): Cyclic Changes in Histomorphology and Hormone Receptor Distribution

“…Transformation zone epithelium is more susceptible to human papillomavirus (HPV) infection and estrogen-induced squamous metaplasia that can lead to cervical carcinoma (Elson et al, 2000). High levels of ER and PR are expressed in transformation zone epithelium in humans (Remoue et al, 2003). Both ERa and PR are expressed throughout the sea lion cervix and vagina surrounding these epithelial transition zones, and similar to dogs, there was little variation in receptor expression in the cervix and vagina throughout the cycle (Vermeirsch et al, 2002).…”